Motor proteins in cells include myosin, which is actin-based, and kinesin, dynein and dynamin, which are microtubule-based (Lillie 1992, Nature 356:358-361). Kinesin has been identified as a transporter of membranous organelles in mammalian neurons. Genes related to kinesin heavy chain have been identified in Schizosaccharomyces pombe and Saccharomyces cerevisiae. Most of the members of the kinesin family are implicated in mechanisms of mitosis or meiosis (Aizawa 1992, J. Cell. Biol. 119:1287-1296).
The Pac10 gene of Saccharomyces cerevisiae, which encodes the heavy chain of members of the kinesin family, is required for viability in the absence of the kinesin-related CIN8 mitotic motor. If deleted with CIN8, an associated family member, the Pac 10/CIN8 double mutation is lethal and presumably prevents separation of the spindle pole bodies (Geiser, J R and Hoyt M A, unpublished data).
Centronuclear myopathy is an X-inked congenital myopathy (MTMI) that has been localized to Xq28 (Harrison's Principles of Internal Medicine, 13 edition, ed. Isselbacher et al., publisher McGraw-Hill, New York, pg 2387). Dahl et al. (1995 Am. J. Hum. Genet. 56:1108-1115) report that a young girl with a clinically moderate form of myotubular myopathy and associated mental retardation was found to carry a cytogenetically detectable deletion in Xq27-q28. Positional cloning of the MTMI locus has been refined to a 600 kb region between the DX5304 and DX5497 markers. Other diseases linked to the Xp27-q28 locus include schizophrenia, X-linked mental retardation associated with Fragile Site FRAXE and anophthalmos.
The neonatal form of centronuclear myopathy is X-linked and presents with severe hypotonia and weakness at birth. Patients may require respiratory assistance and a feeding tube due to swallowing difficulties. This form of the disease is often fatal. The early childhood form presents without difficulty at birth, but motor milestones, such as walking, running and stair climbing, are delayed. In this form the disease may be static or may progress to weakness. A rare form of the disease has an onset in the second or third decade. The early childhood and adult forms appear to have autosomal dominant or recessive inheritance patterns. Patients with the neonatal form of centronuclear myopathy require carefull management for respiratory support and gastric feeding, and patients with the early childhood disorder often require ambulatory aids and orthotic devices and less often wheelchairs.
Schizophrenic disorders are serious mental illnesses that cause significant social, vocational, and personal disability. In the United States there are about 2 million affected individuals and these individuals account for an estimated loss of 20 billion dollars of lost productivity per year (Harrison's Principles of Internal Medicine supra pg. 2414-2415). X chromosome linked mental retardation is the second most common genetic cause of mental retardation (after Down's syndrome) (Pathophysiology, 2nd Edition, Editors McCance et al., publisher, Mosby, St. Louis pg. 1420). Anopthalmos is a developmental defect characterized by mental retardation and a complete absence of the eyes or by the presence of vestigal eyes.
In view of the severity of the diseases associated with the Xq27-q28 locus, including centronuclear myopathy, myotubular myopathy, schizophrenia, X-linked mental retardation associated with Fragile Site FRAXE and anophthalmos, it would be advantageous to provide an early and accurate method for the detection of such diseases. It would also be advantageous to provide therapeutic compositions and methods for prevention and treatment of such diseases.